Is CBLB p.Ser403Leu (c.1208C>T) pathogenic?

CBLB p.Ser403Leu (c.1208C>T) is classified Uncertain significance in CBLB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-30). AlphaMissense: likely pathogenic (0.8464); Very rare (popmax 0.00223%, eas).

How common is CBLB p.Ser403Leu (c.1208C>T) in the general population?

CBLB p.Ser403Leu (c.1208C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CBLB p.Ser403Leu (c.1208C>T)?

AlphaMissense predicts likely pathogenic (score 0.8464) — an in-silico prediction, not a clinical call.

CBLB p.Ser403Leu

c.1208C>T · rs747819451 · VCV2309783

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8464 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8464	likely pathogenic
REVEL	0.796	moderately pathogenic-leaning
SaProt	LLR -14.53	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 164 kb · p 3.4e-12 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,854 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000496% 8/1,611,314 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,854
Finnishnot grpmax-eligible	0.00157%	63,894
European (non-Finnish)	0.000509%	196,463

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CBLB
Protein: p.Ser403Leu
Coding: c.1208C>T
MANE Select: NM_170662
dbSNP: rs747819451
Type: single nucleotide variant
Location: chr3:105720246 (GRCh38)
Gene constraint: LOEUF 0.406 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.88 · 36 PDB

Full CBLB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CBLB p.Arg670Gln Benign/Likely benign ★★ same type
CBLB p.Pro387= Benign ★★ same type
CBLB p.Pro689= Benign/Likely benign ★★ same type
CBLB p.Ser622Thr Benign/Likely benign ★★ same type
CBLB c.2569+1609A>C Uncertain significance ★ same type
CBLB p.Ala176Pro Uncertain significance ★ ⚠ same type
CBLB p.Ala2Glu Uncertain significance ★ ⚠ same type
CBLB p.Ala592Ser Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cblb-p-ser403leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown